JPH01242537A - Production of 2-fluorobiphenyl derivative - Google Patents

Abstract

PURPOSE:To advantageously obtain the subject compound useful as an intermediate for analgesic and antipyretic agents, by isolating and drying a fluoride diazonium salt prepared by diazotizing an aniline derivative and subjecting the resultant fluoride diazonium salt to phenyl coupling reaction with benzene in the presence of an alcohol. CONSTITUTION:An aniline derivative expressed by formula I (X is H or halogen) is diazotized to provide a fluoride diazonium salt expressed by formula II (Y is BF4 or PF6), which is subsequently isolated and dried to afford powder. The resultant powder is then subjected to phenyl coupling reaction with benzene (in an amount of preferably 5-20times used on the diazonium salt) in the presence of an alcohol (preferably a 1-4C alcohol in an amount of 0.5-10 times based on the diazonium salt), preferably in the presence of a catalyst, such as copper or a salt thereof, to afford the aimed 2-fluorobiphenyl derivative expressed by formula III. The above-mentioned method is industrially, economically and advantageously carried out in high yield by using the alcohol without requiring purification.

Description

[Detailed Description of the Invention] [Field of Industrial Application] The present invention relates to a method for producing 2-fluorobiphenyl derivatives, which are important compounds as synthetic intermediates for flurbiprofen, which is known as an antipyretic analgesic. It is something.

[Conventional technology]

Conventionally, as a method for synthesizing various biphenyl derivatives, the Gomberg-Bac reaction, which is a phenyl cuff-pulling reaction of a diazonium salt solution using an alkali, has been used.
hmann-Hey) and JP-A-56-972, which performs diazotization and phenyl coupling reaction simultaneously using acid.
The method described in Publication No. 36 is well known.

[Problem to be solved by the invention]

Among the above-mentioned conventional methods, those using phenyl coupling reaction with an alkali produce a large amount of tar-like by-products, and the yield is extremely low at around 30%.

Next, in the method described in JP-A-56-97236, which involves a phenyl coupling reaction using an acid, raw materials such as organic acids are expensive. In addition, since the reaction is heated, there are many tar-like byproducts, and since acid and excess nitrite are used, nitrates that are difficult to separate are produced as byproducts. Therefore, these conventional methods require a reduction reaction using iron/acetic acid or the like in the purification step, and as a result, a large amount of waste water is generated. The equipment is also severely corroded by acid, making it difficult to select the material for the equipment used to reflux and react under heating. Reactions using isoamyl nitrite have also been described, but this is not industrially viable as the raw material is unstable, very dangerous, and expensive.

[Means to solve the problem]

In conventional synthesis methods, water is generated during the diazotization reaction, so water is inevitably present in the system where the phenyl coupling reaction is occurring, and it is thought that this results in the production of large amounts of tarry byproducts. It will be done.

Therefore, the inventors modified the phenyl coupling reaction with diazonium salts in benzene solution using fluoride diazonium salts, i.e., borohydrofluorides or hexafluorophosphates, which can be isolated as dry salts. As a result of intensive studies on phenyl coupling reactions in non-aqueous systems, they discovered that 2-fluorobiphenyl derivatives can be synthesized in high yields by reacting very quickly by adding alcohol. did.

That is, the present invention provides an aniline derivative represented by the general formula (wherein X represents a hydrogen atom or a halogen atom) obtained by diazotizing it by a known method. and Y is B
After the fluoride diazonium salt represented by F or PF is isolated by filtration, it is dried and used. Then, by mixing benzene with the isolated diazonium salt and then reacting with alcohol, a 2-fluorobiphenyl derivative represented by the general formula (wherein X represents a hydrogen atom or a halogen atom) is produced. be able to.

In this case, in the phenyl coupling reaction, alcohol having 1 to 4 carbon atoms is added to 0.5 to 100% of the diazonium salt.
It is preferable to react with benzene in the presence of twice the weight of the diazonium salt (most preferably 1 to 5 times the weight), and it is preferable to react with benzene in the presence of 5 to 20 times the weight of the diazonium salt. The coupling reaction is preferably carried out in the presence of a catalyst such as copper or a copper salt.

Note that methanol or ethanol is usually preferably used as the above-mentioned alcohol having 1 to 4 carbon atoms. In addition, as a catalyst for the above-mentioned copper or copper salt, copper powder or chloride! 14 is normally used.

[For production]

By using a neutral alcohol instead of an organic acid, the by-products produced in the past are extremely frozen, and nitrates are not produced.If the amount of alcohol is small, the reaction is extremely slow and does not terminate. On the other hand, if the amount of alcohol is large, a reduction reaction occurs and halogenated benzene with a low boiling point is produced as a by-product, resulting in a decrease in yield.

If the water content of the diazonium salt is high, a reduction reaction with alcohol will occur and a low boiling point halogenated benzene will be produced as a by-product, so it is better to use a well-dried diazonium salt.The degree of drying will greatly affect the yield. The fluoride diazonium salt is excellent in that it has low hygroscopicity and can be easily dried simply by heating.

The phenylcampling reaction between benzene and diazonium salt does not progress much even when heated or using a catalyst such as copper or a copper salt. However, when alcohol is added to the system, the reaction at room temperature is caused by a catalyst such as copper or a copper salt. But it progresses very quickly.

〔Effect of the invention〕

The present invention has the following effects.

(1) In the phenyl coupling reaction between diazonium salt and benzene, by using a fluoride diazonium salt which can be used as a dry powder, tar is reduced compared to the conventional reaction in the presence of water. The amount of by-products will be very small. Furthermore, since there is no water in the system, it is possible to use alcohol instead of organic acids as in conventional methods, so there is no generation of nitrates, and there is no need for chemical processes such as reduction.

(2) The phenyl coupling reaction between benzene and diazonium salt hardly progresses even when heated or using a catalyst such as copper or a copper salt, but when alcohol is added to the system as in the case of the present invention, the reaction hardly progresses. Once added, the reaction proceeds very quickly with a catalyst such as copper or a copper salt. Therefore, the reaction can be carried out at room temperature and does not require heating or reflux cooling equipment.

(3) It is economically advantageous because expensive organic acids are not used as raw materials as in the conventional case, and alcohol and benzene can be easily recovered by distillation.

(4) Unlike the conventional case, expensive and unstable raw materials such as isoamyl nitrite are not used as raw materials, which is advantageous both industrially and economically.

〔Example〕

Next, examples of the method for producing 2-fluorobiphenyl derivatives according to the present invention will be given.

Example 1 2-Fluoroaniline 5 in 180 g of 35% hydrochloric acid at 10°C
A mixture of 34.5 g (0.5 mol) of sodium nitrite and 55 g of water was gradually added dropwise to the solution while stirring, while maintaining the temperature at 0°C.

The by-product salts were filtered off, and the filtrate was diluted with 50% fluoroboric acid 1
15 g (0.65 mol) and mix with stirring. The precipitated diazonium salt is filtered off and dried at 80° C. for 3 hours to obtain 98 g of 2-fluorobenzenediazonium tetrafluoroborate.

To 98 g of the diazonium salt obtained in this way, 1 part of benzene was added.
kg and 250 g of methanol are mixed, and 5 g of cuprous chloride is added thereto with stirring.

The reaction temperature is maintained at 30 to 40°C and the reaction is allowed to proceed for 5 hours.

The reaction solution was washed twice with 200g of water to remove benzene by evaporation, and the residue was distilled under reduced pressure to give a boiling point of 136'C/27m.
59.7++ (yield 69.4%) of 2-fluorobiphenyl is obtained with +mHg and a melting point of 73-74°C.

Example 2 9.5 g (0.05 mol) of 4-promo-2-fluoroaniline was added to 18 g of 35% hydrochloric acid at 10°C. Bottle, 0℃
Add 3.5 g of sodium nitrite (0.05 g
mol) and 6 g of water was gradually added dropwise while stirring. Filter out the by-product salts and add 50% ammonium hexafluoride phosphorus to the filtrate. 8? &21.1g (0,065mo
1) and mix with stirring. The precipitated diazonium salt is filtered and dried at 80° C. for 3 hours to obtain 15.0 g of 4-bromo-2-fluorohenzendiazonium hexafluorophosphate.

15.0 g of the diazonium salt thus obtained is mixed with 100 g of benzene and 25 g of methanol, and 0.1 g of cuprous chloride is added thereto with stirring.

The reaction temperature is maintained at 30 to 40°C and the reaction is allowed to proceed for 5 hours.

The reaction solution was washed twice with 20g of water to remove benzene by evaporation, and the residue was distilled under reduced pressure to give a boiling point of 151°C/16mm11
g, 8.97 g (yield 71.5%) of 4-bromo-2=fluorobiphenyl having a melting point of 35-37°C are obtained.

Other Examples synthesized in the same manner as Example 1.2 are summarized in Table 1.

(Margin below) Patent applicant: Morita Chemical Industry Co., Ltd. (2 others) nr=

Claims (1)

[Claims] 1. General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼…………………………
...III (In the formula, X represents a hydrogen atom or a halogen atom.) In the method for producing a 2-fluorobiphenyl derivative, there are general formulas ▲mathematical formulas, chemical formulas, tables, etc.▼……………………
… There are general formulas, mathematical formulas, chemical formulas, tables, etc. obtained by diazotizing the aniline derivative represented by I (in the formula, X represents a hydrogen atom or a halogen atom) by a known method. ......
...II (In the formula, X represents a hydrogen atom or a halogen atom, and Y represents BF_4 or PF_6.) After isolating the fluoride diazonium salt, it is subjected to a phenyl coupling reaction with benzene in the presence of alcohol. A method for producing a 2-fluorobiphenyl derivative, characterized in that: 2. In the phenyl coupling reaction, the number of carbon atoms is 1
2. The method for producing a 2-fluorobiphenyl derivative according to claim 1, wherein the alcohol of 4 to 4 is reacted with benzene in the presence of 0.5 to 10 times the weight of the diazonium salt. 3. The method for producing a 2-fluorobiphenyl derivative according to claim 1, wherein in the phenyl coupling reaction, the reaction is carried out with benzene in an amount 5 to 20 times the weight of the diazonium salt. 4. The method for producing a 2-fluorobiphenyl derivative according to claim 1, wherein the phenyl coupling reaction is carried out in the presence of a catalyst such as copper or a copper salt.